Blood pressure (BP) has a circadian rhythm. I think. A circadian rhythm has a strict definition which I’m not entirely sure BP has met. A circadian rhythm is a cyclic process that repeats every 24 hours (“circa” – around, “diem” – day). Chronobiologists have claimed three distinct characteristics a biological rhythm must possess in order to be classified as a true circadian rhythm. The biological rhythm must be able: 1) to “free run” for ~24 hours, 2) to be entrained, and 3) maintain its period length over a range of temperatures. “Free running” describes how a circadian rhythm operates in the absence of environmental input (referred to as a “zeitgeber” in the literature). This property is the result of a cellular timekeeping system, utilizing several transcriptional-translation feedback loops. Even though these rhythms are endogenous, they’re synchronized, or entrained, by the external environment to match a 24 hour period. Light, food intake timing, and activity are examples of environmental cues that can influence biological circadian rhythms. The other feature of entrainment is phase control – a repetition in behavior pattern. Here, it refers to the ability of the rhythm to oscillate normally every 24 hours.
BP doesn’t fluctuate randomly but follows a characteristic rhythmic pattern – it is higher during the day and lower during the night. This became evident with the use of ambulatory blood pressure monitoring (auto-inflatable cuffs) in the clinic and telemetry implantation in the lab (continuous, real-time blood pressure collection in rodents). These rhythmic changes that occur over a 24 hour period would be the first indication that blood pressure is a circadian rhythm. But, to my knowledge, I’m not sure if the other criteria have been met for blood pressure to be defined as a traditional circadian rhythm. So for now, let’s simply say that a healthy blood pressure exhibits rhythm and leave the circadian part out of it.
The Health Implications of Nondipping BP
Normally, BP dips 10-20% from its average daytime levels4. When it drops less than 10%, it is considered nondipping BP in most of the literature.
Hermida et al, Advanced Drug Delivery Reviews 59 (2007) 904–922.
Nondipping BP can result in significantly higher incidences of vascular events, including increased risk of organ damage, left ventricular hypertrophy, stroke, and retinopathy5. These health detriments worsen with reverse dipping – a situation in which BP increases at night over daytime levels. Chronic nondipping BP increases arterial stiffness, vascular inflammation, and is implicated in kidney disease6. We now know that nondipping BP serves as a treatable, independent risk factor for cardiovascular events, with clinical trials often reporting approximately 27% increased incidence
Mancia G., & Verdecchia P. Circ Res. 2015;116:1034-1045
In fact, this is a reason why type 2 diabetics display significantly higher incidences of cardiovascular events than nondiabetics. Prevalence rates of hypertension in type 2 diabetics are often reported around 75% and as high as 94%, with nondipping BP observed as high as 73%12, 13. And so, this becomes an attractive (and challenging) therapeutic target that is gaining interest, paving the way for chronotherapy. Chronotherapy involves administering a medication to match the body’s natural rhythm. For example, antihypertensives such ACE-inhibitors, angiotensin receptor blockers, and aspirin have been used to effectively lower the incidence of cardiovascular events and reduce mortality by reestablishing dipping BP when given at night compared with the morning14-16. In the last post, I showed some clinical data depicting a 39% decrease in cardiovascular events when antihypertensives were taken at night compared with the morning.
However, much is still unknown about medication timing and their mechanisms of action are still unclear. There is one last perspective on this topic I want to briefly introduce, and that is how the timing of food intake greatly controls BP’s rhythm.
Re-Establishing a Normal Food Intake Pattern Restores BP’s Natural Rhythm
It’s now well established that shift-workers display higher rates of cardiovascular disease than non-shift workers. There are a number of reasons why this could be, many of which are outside of this post’s scope.
Puttonen et al. Scand J Work Environ Health. 2010;36(2):96-108.
However, shift-workers provide us some insight into how altered or flipped activity, food intake, and sleep-wake patterns can affect BP. Modeling disrupted BP is quite difficult to do in the lab, but we have found some relief with the db/db mouse. This is a genetically altered mouse whose leptin receptor has been shortened, rendering it inactive. Thus leptin, a satiety hormone, can’t elicit its effects and this mouse eats continuously. It never receives the signal that it is full. And so, it exhibits a number of metabolic detriments, but interestingly, its BP rhythm is completely disrupted. But, when they are put under conditions when they can only access food during their active (or awake) time, and forced to fast during their rest time, their BP rhythm is completely returned to normal.
Here’s data of precisely that. This is mean arterial pressure (MAP) over the course of 3 days, recorded in real-time, in fully conscious and free moving db/db mice. The light red trace depicts these with free access to food – they can eat whenever they want. They’re hypertensive, and their day to night difference in MAP is minimal. Mice being nocturnal, we expect them to rest during the light phase (white spaces) and be active during the dark (gray bars). The dark red line shows what happens to their MAP when food is only available during their active (dark) period. BP dipping returns, thus establishing a normal rhythm.
Here is that same data, shown as bar graphs. The ALF group is under ad lib conditions – free access to food. The ATRF groups are under restricted feeding conditions. L refers to light phase and D, dark phase. We expect to see blood pressure to be lowest during the light phase, when mice are resting (this would obviously be reversed when translating this data to humans). You can clearly see how this is accomplished, and dipping status returns to normal, by controlling food intake timing.
While I think this data may have immediate application to help mitigate nocturnal hypertension, the true strength lies in the insight we’ve gained between food and circadian rhythm. It was traditionally thought that light exposure had the biggest impact on circadian rhythm entrainment. But, with this and other publications that have recently come out, I’m starting to think that food timing might be a stronger cue. Moving forward, we can begin to tease out the mechanisms by which food restriction works to lower BP and begin asking more questions. An immediate one that comes to mind is: can we time short half-life appetite suppressants as a chronotherapeutic method for nocturnal hypertension?
Hermida, R. C., Ayala, D. E., & Portaluppi, F. (2007). Circadian variation of blood pressure: the basis for the chronotherapy of hypertension. Advanced drug delivery reviews, 59(9-10), 904–922. https://doi.org/10.1016/j.addr.2006.08.003
Hou, T., Su, W., Duncan, M. J., Olga, V. A., Guo, Z., & Gong, M. C. (2021). Time-restricted feeding protects the blood pressure circadian rhythm in diabetic mice. Proceedings of the National Academy of Sciences of the United States of America, 118(25), e2015873118. https://doi.org/10.1073/pnas.2015873118
Puttonen, S., Härmä, M., & Hublin, C. (2010). Shift work and cardiovascular disease – pathways from circadian stress to morbidity. Scandinavian journal of work, environment & health, 36(2), 96–108. https://doi.org/10.5271/sjweh.2894
Mancia, G., & Verdecchia, P. (2015). Clinical value of ambulatory blood pressure: evidence and limits. Circulation research, 116(6), 1034–1045. https://doi.org/10.1161/CIRCRESAHA.116.303755